Siramesine (SRM) is a sigma-2 receptor agonist which has been recently shown to inhibit growth of cancer cells. Fluorescence spectroscopy experiments revealed two distinct binding sites for this drug in phospholipid membranes. More specifically, acidic phospholipids retain siramesine on the bilayer surface due to a high-affinity interaction, reaching saturation at an apparent 1:1 drug-acidic phospholipid stoichiometry, where after the drug penetrates into the hydrocarbon core of the membrane. This behavior was confirmed using Langmuir films. Of the anionic phospholipids, the highest affinity, comparable to the affinities for the binding of small molecule ligands to proteins, was measured for phosphatidic acid (PA, mole fraction of X(PA) = 0.2 in phosphatidylcholine vesicles), yielding a molecular partition coefficient of 240 +/- 80 x 10(6). An MD simulation on the siramesine:PA interaction was in agreement with the above data. Taking into account the key role of PA as a signaling molecule promoting cell growth our results suggest a new paradigm for the development of anticancer drugs, viz. design of small molecules specifically scavenging phospholipids involved in the signaling cascades controlling cell behavior.

1,2-Dimyristoyl-sn-glycero-3-phospho-rac-glycerol (DMPG) at low salt concentrations has a complex endotherm with at least four components and extending over the span of 20 degrees. During this ongoing melting, the solution becomes viscous and scatters light poorly. This multipeak endotherm was suggested to result from the effects of curvature on the relative free energies of gel and fluid DMPG bilayers, further relating to the formation of an intermediate sponge phase between the lamellar gel and fluid phases. Although later studies appear to exclude a connected bilayer network, the relation of the endotherm peaks to curvature remains an appealing hypothesis. This was tested by including in the system both water-soluble small molecules (dimethyl sulfoxide, ethanol, and urea) as well as amphiphiles (myristoyl-lyso-PG, cholesterol, cholesterol-3-sulfate, and dimyristoylglycerol) known to alter the spontaneous curvature of bilayers. All compounds increasing the monolayer positive spontaneous curvature (ethanol, urea, myristoyl-lyso-PG, cholesterol-3-sulfate) increased the temperature span of the intermediate state and elevated the temperature of its dissolution, while all compounds increasing the negative spontaneous curvature (dimethyl sulfoxide, cholesterol, dimyristoylglycerol) had the opposite effect, implying that the intermediate state contains a structure with positive curvature. The results support the view that the intermediate state consists of vesicles with a large number of holes. The viscosity increase could be related to vesicle expansion needed to accommodate the numerous holes.

While much is known about the self-assembly of lipids on nanoscale, our understanding of their biologically relevant mesoscale organization remains incomplete. Here, we show for a cationic gemini lipid a sharp and reversible transition from small vesicles with an average diameter of approximately 40 nm to giant vesicles (GVs) with an average diameter of approximately 11 microm. This transition is dependent on proper [NaCl] and specific temperature. Below this transition and in the vicinity of the air/water interface, a series of mesoscale morphological transitions was observed, revealing complex structures resembling biological membranes. On the basis of microscopy experiments, a tentative [NaCl] versus temperature shape/size phase diagram was constructed. To explain this unprecedented transition, we propose a novel mechanism whereby a specific interaction of Cl(-) counterion with the cationic gemini surfactant initiates the formation of a commensurate solute counterion lattice with low spontaneous curvature. In keeping with the high bending rigidity of NaCl crystal, this tightly associated ionic lattice enslaves membrane curvature and the mesoscale 3-D organization of this lipid.